Dr. Alspaugh is a clinical/research fellow in the division of Infectious Diseases at Duke University. he is pursuing a career in academic medicine with a specific, scientific focus in the pathogenesis of infectious diseases. He has previous research experience in molecular genetics and in the immunology of cryptococcal infections. After his clinical infectious disease training, he has been working under the mentorship of Joseph Heitman and John Perfect studying signal transduction pathways in the human fungal pathogen Cryptococcus neoformans, and has identified that certain signaling elements are associated with pathogenicity in this organism. In his current environment at Duke, which includes regular interaction with other investigators interested in studying pathogenic fungi, he has a unique opportunity to continue his development as a research physician. He will be an active participant in both the Division of Infectious Disease as well as the Departments of Genetics and Pharmacology. Elements of signal transduction pathways are remarkably conserved from fungi to man. Dr. Alspaugh is especially interested in those signaling pathways which are activated in pathogens in response to host factors and which are associated with pathogenicity. Recently, heterotrimeric G- proteins have been identified as signaling elements essential for pathogenicity in the plant fungal pathogens Cryphonectria parasitica and Ustilago maydis. By homologous recombination, Dr. Alspaugh created mutant strains of the human pathogen Cryptococcus neoformans with a functional deletion of GPA1, the gene encoding a G alpha protein homolog. The gpa1 mutant cells were defective in mating and in the ability to express two well-established virulence traits, polysaccharide capsule and melanin. In a rabbit model of cryptococcal meningitis, the gpa1 mutant cells were markedly attenuated for virulence. Reintroduction of the wild-type GPA1 gene suppressed all of the mutant phenotypes, as did the addition of cAMP to the mutant cells. These findings implicate a novel signaling pathway in C. neoformans in which the GPA1 proteins transmits several external signals into the cell and, by regulating cAMP levels, regulates the important cellular processes of mating and pathogenicity. Dr. Alspaugh plans to further evaluate this signaling pathway, identifying upstream receptors and downstream molecules, to beer understand the process of pathogenicity in this organism and other fungi.